Congenital heart diseases and their association with the variant distribution features on susceptibility genes

Su, Wei; Zhu, Ping; Wang, Ruochen; Wu, Qingping; Wang, Mengdie; Zhang, Xiaofeng; Li, Mei; Tang, Juesi; Kumar, Mahesh; Wang, Xianjun; Su, Li; Dong, Nianguo

doi:10.1111/cge.12835

Cited by 44 publications

(45 citation statements)

References 33 publications

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“…NKX, GATA and T-box family members constitute the core regulatory network that is responsible for normal cardiac morphogenesis and are causative genes in CHDs [11, 12]. The GATA family members were characterized by two zinc finger domains and transcriptional activation domains (TADs).…”

Section: Introductionmentioning

confidence: 99%

Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

et al. 2017

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BackgroundCongenital heart disease (CHD) is a common birth defect, and most cases occur sporadically. Mutations in key genes that are responsible for cardiac development could contribute to CHD. To date, the genetic causes of CHD remain largely unknown.MethodsIn this study, twenty-nine candidate genes in CHD were sequenced in 106 patients with Tetralogy of Fallot (TOF) using target exome sequencing (TES). The co-immunoprecipitation (CO-IP) and luciferase reporter gene assays were performed in HEK293T cells, and wild-type and mutant mRNA of ZFPM2 were microinjected into zebrafish embryos.ResultsRare variants in key cardiac transcriptional factors and JAG1 were identified in the patients. Four patients carried multiple gene variants. The novel E1148K variant was located at the eighth Zinc-finger domain of FOG2 protein. The CO-IP assays in the HEK293T cells revealed that the variant significantly damaged the interaction between ZFPM2/FOG2 and GATA4. The luciferase reporter gene assays revealed that the E1148K mutant ZFPM2 protein displayed a significantly greater inhibition of the transcriptional activation of GATA4 than the wild-type protein. The wild-type mRNA and the E1148K mutant mRNA of ZFPM2 were injected into zebrafish embryos. At 48 hpf, in the mutant mRNA injection group, the number of embryos with an abnormal cardiac chamber structure and a loss of left–right asymmetry was increased. By 72 hpf, the defects in the chamber and left–right asymmetry became obvious.ConclusionsWe performed TES in sporadic TOF patients and identified rare variants in candidate genes in CHD. We first validated the E1148 K variant in ZFPM2, which is likely involved in the pathogenesis of CHD via GATA4. Moreover, our results suggest that TES could be a useful tool for discovering sequence variants in CHD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1173-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

et al. 2017

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“…Interestingly, a case of hypoplastic left heart syndrome, who had a NOTCH1 mutation, was reported to have an aunt with HRHS (Durbin et al, ) suggesting that our current understanding of the mechanisms underlying the genetic signaling pathways and their role in these defects is incomplete. It is known that several genes and transcription factors, including Nkx2.5 , Hand2 , Tbx5 , Isl1 , and Foxh1 are reported to have a pattern of high expression in the secondary heart field (Black, ; Steimle & Moskowitz, ; Su et al, ).…”

Section: Discussionmentioning

confidence: 99%

Copy number variants in hypoplastic right heart syndrome

Giannakou

Sicko

Kay

et al. 2018

American J of Med Genetics Pt A

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Hypoplastic right heart syndrome (HRHS) is a rare congenital defect characterized by underdeveloped and malformed structures of the right heart. Familial recurrence of HRHS indicates genetic factors contribute to its etiology. Our study investigates the presence of copy number variants (CNVs) in HRHS cases. We genotyped 42 HRHS cases identified from live births throughout California (2003-2010) using the Illumina HumanOmni2.5-8 array. We identified 14 candidate CNVs in 14 HRHS cases (33%) based on the genes included in the CNVs and their functions. Duplications overlapping part of ERBB4 were identified in two unrelated cases.ERBB4 is a neuregulin receptor with a pivotal role in cardiomyocyte differentiation and heart development. We also described a 7.5 Mb duplication at 16q11-12. Multiple genes in the duplicated region have previously been linked to heart defects and cardiac development, including RPGRIP1L, RBL2, SALL1, and MYLK3. Of the 14 validated CNVs, we identified four CNVs in close proximity to genes linked to the Wnt signaling pathway. This study expands on our previous work supporting the role of genetics in HRHS. We identified CNVs affecting crucial genes and signaling pathways involved in right heart development. ERBB4 and duplication of the 16q11-12 region are important areas for future investigation.

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“…First, the genetic changes associated with many types of CHD, such as point mutation and chromatin abnormality (trisomy 21), remain unclear [1]. Second, environmental factors have been found to be related to CHD [2,3]. Third, maternal folic acid supplementation signi cantly reduces the incidence of CHD through epigenetic programming [4].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation abnormalities of imprinted genes in congenital heart disease: A pilot study

Chang

Wang

Xin

et al. 2020

Preprint

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Background: Congenital heart disease (CHD) is resulted from the interaction of genetic aberration and environmental factors. Imprinted genes, which are regulated by epigenetic modifications, are essential for the normal embryonic development. However, the role of imprinted genes in the pathogenesis of CHD remains unclear.Results: We investigated the effect of imprinted gene methylation on the pathogenesis of CHD. Eighteen imprinted genes that are known to affect early embryonic development were selected and the methylation modification genes were detected by massarray in 27 CHD children and 28 healthy children. Altered methylation of 8 imprinted genes was found, including 2 imprinted genes with hypermethylation of GRB10 and MEST and 6 genes with hypomethylation of PEG10, NAP1L5, INPP5F, PLAGL1, NESP and MEG3. Stratified analysis showed that the methylation degree of imprinted genes was different in different types of CHD. Risk analysis showed that 6 imprinted genes within a specific methylation level range were the risk factor for CHD except MEST and NAP1L5.Conclusion: Altered methylation of imprinted genes is associated with CHD and varies in different types of CHD. Further experiments are warranted to identify the methylation characteristics of imprinted genes in different types of CHD and clarify the pathogenesis mechanism of imprinted genes in CHD.

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Congenital heart diseases and their association with the variant distribution features on susceptibility genes

Cited by 44 publications

References 33 publications

Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

Multiple gene variations contributed to congenital heart disease via GATA family transcriptional regulation

Copy number variants in hypoplastic right heart syndrome

DNA methylation abnormalities of imprinted genes in congenital heart disease: A pilot study

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